Journal of Alzheimer's Disease - Volume 86, issue 3

Authors: Grothe, Jessica | Luppa, Melanie | Dietzel, Jens | Schomerus, Georg | Sommerlad, Andrew | Riedel-Heller, Steffi G. | Röhr, Susanne

Article Type: Research Article

Abstract: Background: Dementia is one of the most common and most severe disorder in old age. In addition to cognitive decline and functional impairment, changes in social functioning occur in the course of dementia. Currently, there is no valid instrument in German language to assess social functioning in individuals with dementia. Objective: We aim to adapt and psychometrically evaluate a German version of the Social Functioning in Dementia Scale (SF-DEM). Methods: First, a multi-step and team-based translation process based on the TRAPD model was performed. Second, we interviewed dyads of individuals with mild dementia and caregivers to …test the internal consistency, test-retest reliability, interrater reliability, construct validity, and acceptance of the German version of the SF-DEM. Results: The internal consistency of the patient-rated (α = 0.72) and the caregiver-rated (α = 0.76) SF-DEM is at an acceptable level. The interrater reliability was excellent for both versions (patients: ICC = 0.98, CI [0.95–0.99]; caregiver: ICC = 0.95, CI [0.89–0.98]) and the test-retest reliability was moderate (patients: ICC = 0.57, CI [0.26–0.77]; caregiver: ICC = 0.58, CI [0.27–0.78]). Caregiver-rated SF-DEM correlated strong with LSNS-6 (rs  = 0.60, p  < 0.01), QoL-AD (marriage: rs  = 0.61, p  < 0.01; friends: rs  = 0.51, p  = 0.01). In addition, the SF-DEM was accepted by the participants. Conclusion: The German SF-DEM is a valid, reliable, and acceptable instrument to assess social functioning in individuals with dementia. Further research should address the psychometric properties in individuals with more severe dementia. Show more

Keywords: Acceptance, dementia, measure, psychometrics, questionnaire, reliability, scale, SF-DEM, social functioning, validity

DOI: 10.3233/JAD-215557

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1231-1241, 2022

Authors: O’Bryant, Sid E. | Zhang, Fan | Petersen, Melissa | Hall, James R. | Johnson, Leigh A. | Yaffe, Kristine | Braskie, Meredith | Vig, Rocky | Toga, Arthur W. | Rissman, Robert A. | for the HABS-HD Study Team

Article Type: Research Article

Abstract: Background: Hispanics are expected to experience the largest increase in Alzheimer’s disease (AD) and AD related dementias over the next several decades. However, few studies have examined biomarkers of AD among Mexican Americans, the largest segment of the U.S. Hispanic population. Objective: We sought to examine proteomic profiles of an MRI-based marker of neurodegeneration from the AT(N) framework among a multi-ethnic, community-dwelling cohort. Methods: Community-dwelling Mexican Americans and non-Hispanic white adults and elders were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T MRI of the …brain. A neurodegeneration MRI meta-ROI biomarker for the AT(N) framework was calculated. Results: Data was examined from n  = 1,291 participants. Proteomic profiles were highly accurate for detecting neurodegeneration (i.e., N +) among both Mexican Americans (AUC = 1.0) and non-Hispanic whites (AUC = 0.98). The proteomic profile of N  + was different between ethnic groups. Further analyses revealed that the proteomic profiles of N  + varied by diagnostic status (control, MCI, dementia) and ethnicity (Mexican American versus non-Hispanic whites) though diagnostic accuracy was high for all classifications. Conclusion: A proteomic profile of neurodegeneration has tremendous value and point towards novel diagnostic and intervention opportunities. The current findings demonstrate that the underlying biological factors associated with neurodegeneration are different between Mexican Americans versus non-Hispanic whites as well as at different levels of disease progression. Show more

Keywords: Alzheimer’s disease, biomarkers, diversity, hispanic, mexican american, mild cognitive impairment, neurodegeneration

DOI: 10.3233/JAD-210543

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1243-1254, 2022

Authors: Wang, Jia | Ma, Si-Fei | Yun, Qi | Liu, Wen-Jun | Zhai, Hong-Ru | Shi, Hou-Zhen | Xie, Lan-Gui | Qian, Jin-Jun | Zhao, Chun-Jie | Zhang, Wei-Ning

Article Type: Research Article

Abstract: Background: Several recent findings have revealed that targeting of cell cycle reentry and (or) progression may provide an opportunity for the therapeutic intervention of Alzheimer’s disease (AD). FOXG1 has been shown to play important roles in pattern formation, cell proliferation, and cell specification. Thus far, the roles of FoxG1 and its involvement in AD are largely unknown. Objective: Our study aimed to explore the intervention effect of FOXG1 on AD pathology and its potential mechanism with a particular focus on cell cycle regulation. Methods: We investigated the association of Foxg1 gene variants with AD-like behavioral …deficits, p21 expression, neuronal apoptosis, and amyloid-β (Aβ) aggregate formation; we further determined whether targeting FOXG1-regulated cell cycle has therapeutic potential in AD. Results: Paralleling AD-like behavioral abnormalities, neuronal apoptosis, and Aβ deposits, a significant reduction in the expression of FOXG1 was observed in APP/PS1 mice at 6 months of age. Using the APP/PS1;Foxg1fl /f l -CreAAV mouse line, we found that FOXG1 potentially antagonized cell cycle reentry by negatively regulating the levels of p21-activated kinase (PAK3). By reducing p21cip 1 -mediated arrest at the G2 stage and regulating cyclin A1- and cyclin B-dependent progression patterns of the cell cycle, FOXG1 blocked neuronal apoptosis and Aβ deposition. Conclusion: These results indicate that FOXG1 contributes to the regulation of the neuronal cell cycle, thereby affecting brain abnormalities in AD. An elevation of the FOXG1 level, either pharmacologically or through other means, could present a therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β deposits, apoptosis, cell cycle, FOXG1, p21cip1

DOI: 10.3233/JAD-215144

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1255-1273, 2022

Authors: Tian, Qu | Bilgel, Murat | Moghekar, Abhay R. | Ferrucci, Luigi | Resnick, Susan M.

Article Type: Research Article

Abstract: Background: Olfactory deficits are early features of preclinical Alzheimer’s disease (AD). Whether olfaction is associated with PET biomarkers among community-dwelling older adults is less clear. Objective: Investigate cross-sectional and longitudinal associations of olfaction with mild cognitive impairment (MCI) and amyloid-β (Aβ) and tau deposition. Methods: We analyzed 364 initially cognitively normal participants (58% women, 24% black) who had baseline olfaction data and subsequent cognitive assessments during an average 2.4-year. A subset of 129 had PET-PiB (Aβ) (n  = 72 repeated) and 105 had 18 F-flortaucipir (FTP)-PET (tau) (n  = 44 repeated). Olfaction was measured using a 16-item Sniffin’ …Sticks Odor Identification Test. The association of olfaction with incident MCI was examined using Cox regression. Associations with PiB-distribution volume ratio (DVR) and FTP-standardized uptake value ratio (SUVR) were examined using partial correlation. We tested whether PiB+/–status modified these associations. Analyses were adjusted for demographics and olfactory test version. Results: 17 (5%) participants developed MCI. Each unit lower odor identification score was associated with 22% higher risk of developing MCI (p  = 0.04). In the PET subset, lower scores were associated with higher mean cortical DVR and DVR in orbitofrontal cortex (OFC), precuneus, and middle temporal gyrus (p ≤0.04). The “olfaction*PiB+/–” interaction in OFC DVR was significant (p  = 0.03), indicating the association was limited to PiB positive individuals. Greater decline in odor identification score was associated with greater increase in anterior OFC DVR and entorhinal tau SUVR (p ≤0.03). Conclusion: Among community-dwelling older adults, poorer olfaction predicts incident MCI and is associated with overall and regional Aβ. Greater olfaction decline is associated with faster Aβ and tau accumulation in olfaction-related regions. Whether olfaction predicts AD-related neurodegenerative changes warrants further investigations. Show more

Keywords: Amyloid-β, olfaction, PET biomarkers, tau

DOI: 10.3233/JAD-210636

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1275-1285, 2022

Authors: Hang, Zhongci | Cai, Shanglin | Lei, Tong | Zhang, Xiaoshuang | Xiao, Zhuangzhuang | Wang, Donghui | Li, Yingxian | Bi, Wangyu | Yang, Yanjie | Deng, Shiwen | Wang, Li | Li, Quanhai | Du, Hongwu

Article Type: Research Article

Abstract: Background: Fecal microbiota transplant (FMT) is a potential treatment approach for many diseases. Alzheimer’s disease (AD) and cancer have been proven to have a specific antagonistic relationship to FMT. Objective: This article aims to explore whether intestinal flora transplantation from cancer individuals can ameliorate cognitive impairment. Methods: Morris water maze and object recognition tests were performed to assess cognitive function after the fecal flora from tumor-bearing and WT mice were transplanted into AD mice by gavage. The effect of flora transplantation on AD was analyzed by thioflavin T staining, western blot, and 16S RNA sequencing. …Results: AD mice with FMT significantly improved short-term memory level and cognitive ability compared with Tg + NaCl group. Inflammatory factors in the plasma were regulated, and Aβ plaques burden in the hippocampus and cortex were decreased. FMT in the tumor-bearing group showed a higher significant amelioration in symptoms compared to the healthy group. 16S RNA sequencing revealed that FMT treatments could reverse the increased Firmicutes and Prevotella and the decreased Bacteroidetes , Bacteroides , and Sutterella in AD mice. AD mice transplanted with tumor-bearing mice feces additionally increased the density of Oscillospira , Odoribacter , and AF12 . Furthermore, the predicted functional analyses showed that the metabolism of inorganic and organic salts in the intestinal flora of AD mice was also reversed by FMT. Conclusion: Intestinal flora transplantation from tumor-bearing mice can ameliorate the cognitive impairment of AD mice. Show more

Keywords: Alzheimer’s disease, cancer, fecal microbiota transplants, intestinal flora

DOI: 10.3233/JAD-215495

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1287-1300, 2022

Authors: Soares, Jelena Zugic | Valeur, Jørgen | Šaltytė Benth, Jūratė | Knapskog, Anne-Brita | Selbæk, Geir | Arefi, Golchin | Gilfillan, Gregor D. | Tollisen, Anita | Bogdanovic, Nenad | Pettersen, Renate

Article Type: Research Article

Abstract: Background: Vitamin D insufficiency has been suggested as a dementia risk factor. Objective: In this cross-sectional, explorative study we investigated whether levels of vitamin D in cerebrospinal fluid (CSF) are lower in patients with positive biomarkers of Alzheimer’s disease (AD) compared to cognitively healthy controls and whether polymorphisms of the vitamin D receptor (VDR) gene, FokI, BsmI, ApaI, and TaqI, are associated with levels of vitamin D in CSF and cognition. Methods: We included 100 patients≥65 years assessed for cognitive impairment and 76 cognitively healthy controls. Levels of 25-hydroxyvitamin D (25(OH)D) in both serum and CSF, …and VDR polymorphisms were analyzed. Results: The mean level of 25(OH)D in serum was 78.6 (SD 28.9) nmol/l. While serum levels of 25(OH)D were not significantly different between the groups, CSF levels of 25(OH)D were significantly lower in patients with positive AD core biomarkers (p  = 0.001) compared to patients without such biomarkers. Individuals with the BsmI major homozygote genotype had significantly lower results on a 10-word delayed recall test (p  = 0.044) and verbal fluency test (p  = 0.013), and individuals with the TaqI major homozygote genotype had significantly lower results on a verbal fluency test (p  = 0.030) compared to individuals with the corresponding minor homozygote genotype. Conclusion: Patients with positive AD core biomarkers have low CSF levels of 25(OH)D, despite sufficient serum levels. CSF levels of 25(OH)D do not seem to be affected by any of the four VDR gene polymorphisms. TaqI and BsmI major homozygote genotypes might be at increased risk for development of cognitive decline. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, cerebrospinal fluid, cognitive function, dementia, polymorphism, single nucleotide, vitamin D, vitamin D3 receptor

DOI: 10.3233/JAD-215536

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1301-1314, 2022

Authors: Wang, Jing | Ding, Ding | Wu, Bei

Article Type: Research Article

Abstract: Background: There has been a rich body of literature on informal caregivers of persons with dementia (PWD). However, little has been discussed on how to facilitate person-centered dementia care in home settings with spouses as primary caregivers. We tend to take it for granted that spouses provide person-centered care for PWD. However, being spouses of PWD and living with them for several decades does not necessarily mean that it is easier for them to provide person-centered dementia care and maintain valued and healthy relationships. Objective: The current study aimed to explore dyadic experiences of PWD and their spousal …caregivers and develop a culturally and contextually-sensitive understanding of person-centered dementia care in home-based settings. Methods: A total of 20 dyads of PWD and their care partners were selected for this study. A trained qualitative interviewer conducted a one-on-one interview with each participant with dementia and their care partners separately. We adopted both conventional and directed content analyses. Results: Our findings provide examples of care partners provide person-centered care, resulting in a profound positive impact on their wellbeing. Adaptive leadership and collaborative work emerged as a key finding in facilitating person-centered dementia care. Cultural relevancy of person-centered dementia care was also interpreted from the data. The study findings provide implications for the evolving of person-centered dementia care model in home-based settings. Conclusion: Findings from this study highlight the significance of facilitating person-centered dementia care in home-based settings between PWD and their primary family caregivers. Show more

Keywords: Dementia care, informal caregivers, person-centered care, theoretical model

DOI: 10.3233/JAD-215612

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1315-1322, 2022

Authors: Saji, Naoki | Murotani, Kenta | Sato, Naoyuki | Tsuduki, Tsuyoshi | Hisada, Takayoshi | Shinohara, Mitsuru | Sugimoto, Taiki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Previous studies have demonstrated associations between gut microbiota, microbial metabolites, and cognitive decline. However, relationships between these factors and neurofilament light chain (NfL; a disease-nonspecific biomarker of neural damage) remain controversial. Objective: To evaluate the associations between plasma NfL, gut microbiota, and cognitive function. Methods: We performed a cross-sectional sub-analysis of data from our prospective cohort study that was designed to investigate the relationship between gut microbiota and cognitive function. Patients who visited our memory clinic were enrolled and demographics, dementia-related risk factors, cognitive function, brain imaging, gut microbiomes, and microbial metabolites were assessed. We …evaluated the relationships between the gut microbiome, microbial metabolites, and plasma NfL. Moreover, the relationships between plasma NfL and cognitive function were assessed using multivariable logistic regression analyses. Results: We analyzed 128 participants (women: 59%, mean age: 74 years). Participants with high (above the median) plasma NfL concentrations tended to be older, women, and hypertensive and have a history of stroke, chronic kidney disease, and dementia. Plasma NfL was also associated with cerebral small vessel disease. However, plasma NfL levels were not significantly correlated with gut microbial metabolites. Multivariable analyses revealed that a higher plasma NfL concentration was independently associated with the presence of dementia (odds ratio: 9.94, 95% confidence interval: 2.75–48.2, p  < 0.001). Conclusion: High plasma NfL concentration was independently associated with the presence of dementia as previously reported. However, plasma NfL levels were not significantly correlated with gut microbial metabolites in this preliminary study. Show more

Keywords: Biomarkers, cerebral small vessel disease, cognitive decline, dementia, gut microbiota

DOI: 10.3233/JAD-215141

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1323-1335, 2022

Authors: Álvarez-Sánchez, Lourdes | Peña-Bautista, Carmen | Baquero, Miguel | Cháfer-Pericás, Consuelo

Article Type: Research Article

Abstract: Background: Single molecule array (SIMOA) and other ultrasensitive detection technologies have allowed the determination of blood-based biomarkers of Alzheimer’s disease (AD) for diagnosis and monitoring, thereby opening up a promising field of research. Objective: To review the published bibliography on plasma biomarkers in AD using new ultrasensitive techniques. Methods: A systematic review of the PubMed database was carried out to identify reports on the use of blood-based ultrasensitive technology to identify biomarkers for AD. Results: Based on this search, 86 works were included and classified according to the biomarker determined. First, plasma amyloid-β showed …satisfactory accuracy as an AD biomarker in patients with a high risk of developing dementia. Second, plasma t-Tau displayed good sensitivity in detecting different neurodegenerative diseases. Third, plasma p-Tau was highly specific for AD. Fourth, plasma NfL was highly sensitive for distinguishing between patients with neurodegenerative diseases and healthy controls. In general, the simultaneous determination of several biomarkers facilitated greater accuracy in diagnosing AD (Aβ42 /Aβ40 , p-Tau181/217). Conclusion: The recent development of ultrasensitive technology allows the determination of blood-based biomarkers with high sensitivity, thus facilitating the early detection of AD through the analysis of easily obtained biological samples. In short, as a result of this knowledge, pre-symptomatic and early AD diagnosis may be possible, and the recruitment process for future clinical trials could be more precise. However, further studies are necessary to standardize levels of blood-based biomarkers in the general population and thus achieve reproducible results among different laboratories. Show more

Keywords: Alzheimer’s disease, biomarker, blood, digital immunoassay, ELISA, plasma, protein, SIMOA

DOI: 10.3233/JAD-215093

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1337-1369, 2022

Authors: Weinstein, Galit | O’Donnell, Adrienne | Davis-Plourde, Kendra | Zelber-Sagi, Shira | Ghosh, Saptaparni | DeCarli, Charles S. | Thibault, Emma G. | Sperling, Reisa A. | Johnson, Keith A. | Beiser, Alexa S. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer’s disease pathology is unclear. Objective: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology. Methods: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011–2014) and 2 (2008–2011), respectively. Participants underwent 11 C-Pittsburgh Compound-B amyloid and 18 F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information …on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons. Results: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 > 1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p  = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p  < 0.001; β= 1.60±0.53, p  = 0.007, and β= 1.59±0.47, p  = 0.003 and β= 1.60±0.42, p  = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p  < 0.001; β= 1.59±0.38, p  < 0.001, and β= 1.52±0.54, p  = 0.008, respectively). Conclusion: This study suggests a possible association between liver fibrosis and early Alzheimer’s disease pathology, independently of cardio-metabolic risk factors. Show more

Keywords: Alzheimer’s disease, amyloid-β, liver fibrosis, non-alcoholic fatty liver disease, positron emission tomography

DOI: 10.3233/JAD-215409

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1371-1383, 2022

Authors: Liu, Ziming | Paek, Eun Jin | Yoon, Si On | Casenhiser, Devin | Zhou, Wenjun | Zhao, Xiaopeng

Article Type: Research Article

Abstract: Background: People with Alzheimer’s disease (AD) often demonstrate difficulties in discourse production. Referential communication tasks (RCTs) are used to examine a speaker’s capability to select and verbally code the characteristics of an object in interactive conversation. Objective: In this study, we used contextualized word representations from Natural language processing (NLP) to evaluate how well RCTs are able to distinguish between people with AD and cognitively healthy older adults. Methods: We adapted machine learning techniques to analyze manually transcribed speech transcripts in an RCT from 28 older adults, including 12 with AD and 16 cognitively healthy older …adults. Two approaches were applied to classify these speech transcript samples: 1) using clinically relevant linguistic features, 2) using machine learned representations derived by a state-of-art pretrained NLP transfer learning model, Bidirectional Encoder Representation from Transformer (BERT) based classification model. Results: The results demonstrated the superior performance of AD detection using a designed transfer learning NLP algorithm. Moreover, the analysis showed that transcripts of a single image yielded high accuracies in AD detection. Conclusion: The results indicated that RCT may be useful as a diagnostic tool for AD, and that the task can be simplified to a subset of images without significant sacrifice to diagnostic accuracy, which can make RCT an easier and more practical tool for AD diagnosis. The results also demonstrate the potential of RCT as a tool to better understand cognitive deficits from the perspective of discourse production in people with AD. Show more

Keywords: Alzheimer’s disease, early diagnosis, natural language processing, transfer learning

DOI: 10.3233/JAD-215137

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1385-1398, 2022

Authors: Hua, Xue | Church, Kevin | Walker, William | L’Hostis, Philippe | Viardot, Geoffrey | Danjou, Philippe | Hendrix, Suzanne | Moebius, Hans J.

Article Type: Research Article

Abstract: Background: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer’s disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss. Objective: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton. Methods: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n  = 48; age, 33.4±6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects …(n  = 29; age, 63.8±4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n  = 11; age, 69.2±7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement. Results: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p  = 0.027; n  = 7 at 40 mg fosgonimeton versus n  = 4 placebo). Conclusion: These results support the continued development of fosgonimeton as a novel therapeutic for people with AD and dementia. The fast-onset normalization of ERP P300 latency in AD subjects suggests enhancement of synaptic function and potential procognitive effects. Show more

Keywords: ATH-1001, ATH-1017, Alzheimer’s disease, dementia, fosgonimeton, hepatocyte growth factor, electroencephalography, event-related potentials, P300 component, neurotrophic factor

DOI: 10.3233/JAD-215511

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1399-1413, 2022

Authors: Chan, Carol K. | Pettigrew, Corinne | Soldan, Anja | Zhu, Yuxin | Wang, Mei-Cheng | Albert, Marilyn | Rosenberg, Paul B. | and the BIOCARD Research Team

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) among cognitively normal older adults are increasingly recognized as risk factors for cognitive decline and impairment. However, the underlying mechanisms remain unclear. Objective: To examine whether biomarkers of Alzheimer’s disease (amyloid burden) and cerebrovascular disease (white matter hyperintensity (WMH) volume) modify the association between NPS and cognitive decline among cognitively unimpaired older adults. Methods: Analyses included 193 cognitively unimpaired participants (M age = 70 years) from the BIOCARD study, including 148 with PET amyloid and WMH biomarker data. NPS were measured with Neuropsychiatric Inventory and Geriatric Depression Scale scores. Linear mixed effects models …were used to examine the association between baseline NPS and longitudinal cognitive trajectories (M follow-up = 3.05 years), using separate models for global, episodic memory, and executive function cognitive composite scores. In a subset of individuals with biomarker data, we evaluated whether WMH or cortical amyloid burden modified the relationship between NPS and cognitive change (as indicated by the NPS×biomarker×time interactions). Results: Higher baseline NPS were associated with lower executive function scores, but not a faster rate of decline in executive function. NPS symptoms were unrelated to the global or episodic memory composite scores, and there was little evidence of a relationship between NPS symptoms and cognitive change over time. The associations between NPS and cognitive decline did not differ by amyloid or WMH burden, and NPS were unrelated to amyloid and WMH burden. Conclusion: These results suggest that the effect of neuropsychiatric symptoms on executive dysfunction may occur through mechanisms outside of amyloid and cerebrovascular disease. Show more

Keywords: Alzheimer’s disease, amyloid, depression, mild behavioral impairment, neuropsychiatric symptoms, white matter hyperintensities

DOI: 10.3233/JAD-215267

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1415-1426, 2022

Authors: Tsamou, Maria | Carpi, Donatella | Pistollato, Francesca | Roggen, Erwin L.

Article Type: Research Article

Abstract: Background: A complex network of aging-related homeostatic pathways that are sensitive to further deterioration in the presence of genetic, systemic, and environmental risk factors, and lifestyle, is implicated in the pathogenesis of progressive neurodegenerative diseases, such as sporadic (late-onset) Alzheimer’s disease (sAD). Objective: Since sAD pathology and neurotoxicity share microRNAs (miRs) regulating common as well as overlapping pathological processes, environmental neurotoxic compounds are hypothesized to exert a risk for sAD initiation and progression. Methods: Literature search for miRs associated with human sAD and environmental neurotoxic compounds was conducted. Functional miR analysis using PathDip was performed to …create miR-target interaction networks. Results: The identified miRs were successfully linked to the hypothetical starting point and key events of the earlier proposed tau-driven adverse outcome pathway toward memory loss. Functional miR analysis confirmed most of the findings retrieved from literature and revealed some interesting findings. The analysis identified 40 miRs involved in both sAD and neurotoxicity that dysregulated processes governing the plausible adverse outcome pathway for memory loss. Conclusion: Creating miR-target interaction networks related to pathological processes involved in sAD initiation and progression, and environmental chemical-induced neurotoxicity, respectively, provided overlapping miR-target interaction networks. This overlap offered an opportunity to create an alternative picture of the mechanisms underlying sAD initiation and early progression. Looking at initiation and progression of sAD from this new angle may open for new biomarkers and novel drug targets for sAD before the appearance of the first clinical symptoms. Show more

Keywords: Adverse outcome pathway, Alzheimer’s disease, key events, miRs, neurotoxicity

DOI: 10.3233/JAD-215434

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1427-1457, 2022

Authors: Aksnes, Mari | Aass, Hans Christian D. | Tiiman, Ann | Terenius, Lars | Bogdanović, Nenad | Vukojević, Vladana | Knapskog, Anne-Brita

Article Type: Research Article

Abstract: Background: Neuroinflammation is a central component of Alzheimer’s disease (AD) and correlates closely with amyloid pathology. Markers of inflammation such as cytokines, and amyloidogenic aggregates, so-called nanoplaques, are both promising biomarker candidates for AD. We have previously shown that there is a relationship between the levels of nanoplaques and cytokines in cerebrospinal fluid, but it is unknown whether this association extends to serum. Objective: Investigate in a naturalistic memory clinic cohort whether the associations between nanoplaques and cytokines in the cerebrospinal fluid extends to serum. Methods: We collected serum from 49 patients assessed for cognitive complaints …at the Oslo University Hospital Memory Clinic (15 with clinical AD). We assessed the levels of serum nanoplaques with the novel Thioflavin-T fluorescence correlation spectroscopy (ThT-FCS) assay. Serum levels of nine cytokines (eotaxin-1, granulocyte colony-stimulating factor [G-CSF], interleukin [IL]-6, IL-7, IL-8, monocyte chemoattractant protein-1 (MCP-1), gamma induced protein 10 (IP-10), macrophage inflammatory protein [MIP]-1α, and MIP-1β) were quantified with a multiplex assay and read on a Luminex IS 200 instrument. Results: Serum nanoplaques were not increased in clinical AD patients compared to non-AD memory clinic patients and nanoplaques were not associated with any cytokines. The cytokines IL-8 and G-CSF were increased in patients with clinical AD compared to non-AD patients. Conclusion: In this small pilot study, serum nanoplaques were not associated with serum cytokines. Nanoplaque levels could not be used to separate clinical AD patients from non-AD patients in this unselected memory clinic cohort. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid-β peptide, biomarkers, cytokines, fluorescence, serum, Thioflavin T

DOI: 10.3233/JAD-215504

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1459-1470, 2022

Authors: Kundu, Payel | Zimmerman, Benjamin | Quinn, Joseph F. | Kaye, Jeffrey | Mattek, Nora | Westaway, Shawn K. | Raber, Jacob

Article Type: Research Article

Abstract: Background: α-klotho might play a role in neurodegenerative diseases. Objective: To determine levels of α-klotho and apoE in serum and cerebrospinal fluid (CSF) samples and their relationship with the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Methods: All subjects were between age 39 to 83+ (n  = 94). CDR and MMSE were administered to all participants. CSF was collected in the early afternoon by lumbar puncture. Results: Serum and CSF levels of α-klotho are positively correlated and both predict scores on the MMSE and CDR, regardless of sex or apoE4 status. …Conclusion: Our results demonstrate that α-klotho may be an important biomarker of cognitive health and neurodegeneration, and that relatively non-invasive sampling of α-klotho from serum is likely highly reflective of CSF levels. Show more

Keywords: α-klotho, apoE, cerebrospinal fluid, Clinical Dementia Rating, Mini-Mental State Examination, serum

DOI: 10.3233/JAD-215719

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1471-1481, 2022

Article Type: Correction

DOI: 10.3233/JAD-229002

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1483-1483, 2022